Coronary heart disease remains the leading cause of morbidity and mortality in the United States and the developed world. Although the current “gold standard” for assessing coronary artery disease (CAD) is angiography, it has serious limitations in evaluating the functional significance of intermediate coronary lesions (comprising 30-70% stenosis). Coronary angiography relies on a visual interpretation of coronary anatomy. A number of studies have documented the large intra- and inter-observer variability that results from visual grading of coronary stenotic lesions. Moreover, studies have shown a lack of correlation between the angiographic delineated stenosis with their physiologic severity on coronary flow. This stems from the highly non-linear relation between the degree of stenosis and the change in blood flow. Typically, the blood flow remains unchanged until the degree of stenosis reaches a critical range (typically >80%), at which point the decrease in flow is quite dramatic. Lesions that are not functionally significant (i.e., do not reduce the flow) may not need treatment. Hence, there is a need for complementary methods to conventional coronary arteriograms that combine coronary anatomy and physiology to assess CAD accurately.
Blood vessel diameter or cross-sectional area gives anatomic measures of stenosis severity. Coronary blood flow, on the other hand, reflects coronary hemodynamic function and can be used to assess functional severity of stenosis through parameters such as coronary flow reserve (CFR) and fractional flow reserve (FFR). CFR is defined as the ratio of hyperemic (induced by pharmacological agents) to resting flow in a coronary artery. It has been previously found that a significant stenosis leading to inducible ischemia occurs when CFR has a value less than 2.0. Normally, the coronary circulation has a flow reserve of 3-5 times that of normal resting blood flow. This reserve stems from the tone of small blood vessels (microvascular bed). In disease, the microvascular bed dilates and uses some of its reserve to compensate for the pressure drop to the stenosis. Hence, a low CFR value can characterize disease in the epicardial arteries or the distal resistive microvascular bed.
Myocardial fractional flow reserve, the ratio of distal to proximal pressure of a lesion under hyperemic conditions, is an important index of coronary stenosis because it has lower variability and higher reproducibility than CFR and hyperemic stenosis resistance (HSR). The current method for the measurement of FFR requires the use of a pressure wire inserted through the stenosis (Kern, et al., Circulation 87: 1354-1367; Kern, et al., J. Am. Coll. Cardiol. 55: 173-185). Although recent advancements in sensor guidewire technology allow simultaneous measurement of distal pressure and flow velocity, there are still high variability and instability of flow velocity, occasional signal shift for pressure and guidewire obstruction of flow. The placement of pressure wire near a stenosis can also lead to overestimation of FFR. To avoid these operational shortcomings and the expense of pressure wire, a non-invasive method only based on hyperemic coronary blood flow and lesion geometry would be preferable.
In vessel segments without a stenosis, the pressure-flow curve is nearly linear in the physiological pressure range during maximal vasodilation. The linear pressure-flow relation is altered when a stenosis is present. A quadratic relation between pressure gradient (ΔP) and flow rate was shown as: ΔP=A·Q+B·Q2, where A and B were empirical parameters determined through a curve fit of experimental data (Young, et al., J. Biomech. 6: 395-410; Young, et al., J. Biomech. 6: 547-559; Seeley, et al., J. Biomech. 6: 439-448; and Young, et al., Circ. Res. 41: 99-107). Although the quadratic relation has been experimentally validated for coronary stenosis (Siebes, et al., Circulation, 109: 756-762), the empirical parameters (A and B) are not known at priori. Hence, there is a need for a physically non-invasive physics-based model of ΔP or FFR that does not contain any empirical parameters and is specific to geometry and dynamics of coronary artery lesions. Such model would allow the prediction of functional lesion severity non-invasively to guide percutaneous coronary intervention.